CZ279339B6 - Triazole derivatives, process of their preparation , intermediates of these processes, a pharmaceutical antifungal preparation and the use of the aforementioned compounds - Google Patents

Abstract

Antifungal compounds of formula (I) wherein R is phenyl substituted with one to three halogens, -CF.sub.3 on -OCF3, R.sup.1, is alkyl C1 to C4, R5 is hydrogen or alkyl of 1 to 4 carbon atoms, X is CH or N and Y is fluorine or chlorine, and the salts thereof are acceptable. pharmaceutical aspect. The compounds can be used for both topical and systemic administration to suppress fungal diseases. The invention also relates to a process for the preparation of these substances and pharmaceutical compositions containing them

Description

Triazole. a compound of formula (I) wherein: R-phenyl is substituted with 1 to 3 substituents, each of which is independently selected from the group consisting of halogens, -CF 3 and -OCF 3, R ¹ -C ¹ -C ₄ alkyl R ^{2 is} hydrogen or C 1 -C 4 alkyl, X is CH or N, and Y is fluoro or chloro. The invention also relates to processes for the preparation of these compounds and intermediates of the process of formulas IV, VI and XI, wherein the symbols are as defined above and Z ² and Z ³ are independently hydrogen and removable groups, both of which cannot be both. hydrogen atom. Also included are pharmaceutical compositions containing the diluted triazole derivatives and the use of these compounds in the manufacture of a medicament having antifungal activity.

clay

AND,

Triazole derivatives, processes for their preparation, intermediates of these processes, a pharmaceutical antifungal agent and the use of said compounds

Technical field

The present invention relates to novel triazole derivatives, in particular 2-aryl-3- (3-halopyridin-4-yl or 5-halopyridin-4-yl) -1- (1H-1,2,4-triazol-1-yl) alkane -2-ol derivatives, methods for preparing these compounds, intermediates used in these processes, a pharmaceutical antifungal agent, and the use of the above compounds and compositions for treating fungal infections in animals including humans.

BACKGROUND OF THE INVENTION

With respect to the prior art, some triazole derivatives are generally mentioned in European Patent No. 357 241, but none of these derivatives are specifically mentioned as having an antifungal effect, nor are they directly mentioned in the Examples section.

SUMMARY OF THE INVENTION

The present invention provides triazole derivatives of the formula I:

(I) in which:

R is phenyl, substituted with from 1 to 3 substituents, each of which is substituted with 1 to 3 substituents; these substituents are independently selected from the group consisting of halogens, -CF _3, and -OCF ₃ ,

Ί

R represents an alkyl group having 1 to 4 carbon atoms,

R ² represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms,

X is CH or N, and

Y represents a fluorine or chlorine atom, and pharmaceutically acceptable salts thereof.

Preferred are those triazole derivatives of formula I wherein R is phenyl substituted with 1 or 2 halogen substituents, which are preferably independently selected from the group consisting of fluorine and chlorine.

-1GB 279339 B6

In particular, preferred compounds of the invention are those compounds of formula I wherein R is 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl, or 2,4-dichlorophenyl, especially those wherein the substituent R is 2-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl.

In said compounds, preferably R ¹ represents a methyl group and R ² represents a hydrogen atom or a methyl group, most preferably a hydrogen atom.

Also preferred according to the invention are triazole derivatives in which X represents a nitrogen atom and further those compounds in which Y represents a fluorine atom.

The compounds of the formula I according to the invention have a surprisingly high antifungal activity, in particular against Aspergillus spp., Which is based on unexpectedly good pharmacokinetic properties resulting in a longer half-life (t 1/2).

In these compounds, halogen is generally understood to mean fluorine, chlorine, bromine or iodine, wherein the alkyl radicals containing 3 or 4 carbon atoms may be branched or straight chain.

The pharmaceutically acceptable salts of the compounds of formula I include non-toxic acid addition salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates or hydrogen sulfates, phosphates or hydrogen phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, benzoates, methanesulfonates, benzenesulfonates and p-toluenesulfonates. For a summary of these pharmaceutically acceptable salts, see Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

In case that R ¹ and R ² have different meanings, and the compounds of formula I of at least two chiral centers designated with an asterisk in the following formula * and can exist as at least two diastereoisomeric pairs of enantiomers, which can be represented by the following formula I:

(AND)

The present invention includes both the individual stereoisomers of the compounds of Formula I and mixtures thereof. These diastereoisomers may be separated in a conventional manner, for example, by fractional crystallization, chromatographic techniques, or high pressure chromatography (HPLC), from the diastereoisomeric mixture of the compound.

-2GB 279339 B6

Or a salt of the compound or a derivative thereof. The individual enantiomer may also be prepared from the corresponding optically pure intermediate or by resolution by HPLC, starting from the racemate using a suitable chiral carrier, or by fractional crystallization of the diastereoisomeric salts prepared by reaction of the racemate with a suitable optically active acid, such as 1R - (-) - or 1S - (+) - 10-camphorsulfonic acid.

Preferred compounds of the invention wherein R ² represents a hydrogen atom, the 2R, 3S- configuration, i.e.:

are the compounds in which they have

Particularly preferred according to the invention are triazole derivatives of the general formula I selected from the group consisting of: 2R, 3S-2- (2,4-difluorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1) 2,4-triazol-1-yl) butan-2-ol, 2R, 3S-2- (2-chlorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1 H-1,2, 4-Triazol-1-yl) butan-2-ol, 2R, 3S-2- (2-fluorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1,2,4-triazole) 1-yl-butan-2-ol, 2R, 3S-2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazole- 1-yl) butan-2-ol, 2R, 3S-2- (2,4-dichlorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1) -yl) butan-2-ol, and pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical antifungal composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

In the case of the pharmaceutical antifungal, the compound of formula I is preferably complexed with a hydroxyalkyl derivative of cyclodextrin, wherein said hydroxyalkyl derivative is preferably a hydroxypropyl derivative and said cyclodextrin is alpha-cyclodextrin or beta-cyclodextrin.

The present invention also includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a medicament.

SUMMARY OF THE FIRST PROCEDURE FOR PREPARING THE COMPOUNDS OF Formula

According to the present invention, the reaction comprises reacting the 1'-deprotonated form of the compound of formula (II):

(Π) in which R ¹ , R ² , X and Y have the same meaning as given above with a compound of formula III:

(III) wherein R is as defined above, optionally followed by converting the compound of formula (I) so obtained into a pharmaceutically acceptable salt thereof.

Preferably, the deprotonated form is a lithium, sodium or potassium salt of a compound of Formula II.

The second process for the preparation of the compounds of the formula I according to the invention consists in reacting a compound of the formula IV or VI:

in which they have

R, R ¹ , R ² , X and Y have the same meaning as claimed, and as noted above in this

Z represents a leaving group, either with the basic salt of 1H-1,2,4-triazole or with 1H-1,2,4-triazole

Optionally, followed by conversion of a compound of formula (I) so obtained into a pharmaceutically acceptable salt thereof.

Preferably, in the starting compound of formula (VI) used, Z is chloro, bromo, or C 1 -C 4 alkanesulfonyloxy. Said base salt of 1H-1,2,4-triazole is preferably either a sodium salt, a potassium salt or a tetra-n-butylammonium salt, wherein said particularly present base is preferably sodium carbonate or potassium carbonate. More preferred is the use of a compound of formula IV.

In a preferred embodiment of the invention, compounds of formula IA are prepared:

(IA) in which they have

R, R, R and Y have the same meaning as above, or a pharmaceutically acceptable salt thereof, wherein the compound of formula XI is reduced:

Ί 9 in which R, R, R ⁶ and Y have the same meaning as above, and

Z ² and Z ³ are each independently selected from the group consisting of hydrogen and selectively removable groups by reduction, with the proviso that Z ² and Z ^J cannot both be hydrogen simultaneously, optionally followed by conversion of a compound of formula IA to a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the process, a compound of formula XI is used wherein Z ² is a group which can be selectively removed by reduction, and Z ³ is a hydrogen atom,

In particular, the group which can be selectively removed by reduction is a halogen atom, preferably chlorine.

This reduction is preferably carried out by hydrogenolysis using palladium on activated carbon as a catalyst, particularly in the presence of sodium acetate.

The present invention also includes compounds of formula IV or VI:

wherein R, R ¹ , R ² , X and Y are as defined above, and

Z is a leaving group as intermediates in the process for preparing the compound of formula (I) of the invention.

In said compound of formula (VI), Z is preferably a chlorine, bromine or alkanesulfonyloxy group having 1 to 4 carbon atoms.

The present invention also includes a compound of formula XI:

(XI) in which the substituents R, R ¹ , R ² and Y have the same meaning as above, and

Z ² and Z ³ are each independently selected from the group consisting of hydrogen atom and groups which can be selectively removed by reduction, provided that Z and Z cannot both be hydrogen as an intermediate of the process for the preparation of a compound of formula I according to the invention.

-6GB 279339 B6

In this compound, preferably the group which can be selectively removed by reduction is a helogen atom.

It is also preferred that Z ² represents a chlorine atom and Z ³ represents a hydrogen atom.

The process for preparing the compounds of the invention, intermediates and other derivatives and substances related to these processes will be described in more detail below.

Scheme 1

1) base, solvent

(III) compound (I) in which R, R, R, X and Y have the same meaning as above.

Typically, the compound of formula II is deprotonated by the addition of about one equivalent of a suitable base such as lithium diisopropylamide or sodium or potassium bis (trimethylsilyl) amide and the resulting salt, preferably lithium, sodium or potassium, is reacted in situ with ketone III. The reaction is carried out at a temperature of -80 to -50 ° C, preferably -70 to -60 ° C in a suitable organic solvent such as tetrahydrofuran, toluene or diethyl ether under an inert gas atmosphere such as nitrogen or argon.

The starting materials of formula (II) are either known compounds, as described, for example, in D. L. Comins et al., Heterocycles, 22, 339 (1984), or can be obtained by conventional literature procedures. The starting materials of the formula III are either known, for example from European Patent Specifications 44 605 and 69 442, or from British Patent Specification 1,464,224, or they can be obtained by the methods described in said publications.

2) All compounds of formula I can also be prepared according to Scheme 2 below.

-7GB 279339 B6

Scheme 2:

a basic salt of a compound of the formula

solvents or

AT

base and solvent

Compound of Formula I.

Ί 9

In the scheme, R, R, R, X and Y have the meanings given in Formula I and Z is a readily cleavable group such as chlorine, bromine or C 1 -C 4 alkanesulfonyloxy such as methanesulfonyloxy. Examples of suitable basic salts of 1H-1,2,4-triazole are alkali metal salts, preferably sodium and potassium salts, and tetraalkylammonium salts, preferably tetra-n-butylammonium salt (U.S. Pat. No. 4,259,505).

The reaction is preferably carried out using the epoxide of formula IV as the starting material. When a compound of formula (VI) is used as the starting material, this is probably because the corresponding epoxide of formula (IV) is required to be formed at least partially in situ under the reaction conditions. Thus, this process is similar to the process of starting with the epoxide of formula IV.

When the basic salt of 1H-1,2,4-triazole is used, the reaction is typically carried out at room temperature to 100 ° C, in the case of the sodium salt of 1H-1,2,4-triazole, preferably at 60 ° C. ° C and using the corresponding tetra-n-butylammonium salt preferably at room temperature in a suitable organic solvent, for example Ν, Ν-dimethylformamide or tetrahydrofuran.

The reaction may also be carried out using 1H-1,2,4-triazole in the presence of a suitable base such as sodium or potassium carbonate, preferably at a temperature of 50 to 100 ° C in a suitable solvent such as Ν, Ν-dimethylformamide, methanol or mixture of water and acetone.

-8GB 279339 B6

Intermediates of formulas (IV) and (VI) may be prepared in a conventional manner as summarized in Schemes 3 and 4 below:

Scheme 3

1) base, solvent ------- >-->

{Π)

(VI)

(IV)

-9A

In the above scheme, R, R ¹ , R ² , X and Y have the meanings given in formula (I) and Z is an easily cleavable group, preferably a chlorine or bromine atom.

In a typical procedure, the compound of formula II is deprotonated by the addition of about one equivalent of a suitable base such as lithium diisopropylamide or sodium or potassium bis (trimethylsilyl) amide and the resulting organometallic intermediate is reacted in situ with the compound of formula V. at a temperature of -80 to -50, preferably -70 ° C in a suitable organic solvent, for example tetrahydrofuran, toluene or diethyl ether, and under an inert gas atmosphere, for example nitrogen or argon. The resulting compound of formula (VI) does not need to be isolated and can be cyclized in situ after a period of stirring at a higher temperature, for example at room temperature, to give the oxirane of formula (IV).

A compound of formula VI wherein Z is chlorine or bromine can also be prepared by reacting an epoxide of formula IV with the appropriate hydrogen halide under anhydrous conditions.

-10GB 279339 B6

Scheme 4

t (where R = C, -C, alkyl)

I 4

(where ΓΓ = C, "C ₄ alkyl")

-11EN 279339 B6

In the scheme, R, R ¹ , R ² , χ and Y have the meanings given in formula I and Z ¹ is a leaving group, for example a chlorine, bromine, iodine or methanesulfonyloxy group.

Typically, compounds of formulas VIII, IX or X may be prepared directly from an ester of formula VII by reaction with an organometallic intermediate obtained by deprotonation of a compound of formula

or

wherein R ¹ , R ² , X and Y are as defined in formula I with an approximately equivalent amount of a suitable base, for example lithium diisopropylamide or sodium bis (trimethylsilyl) amide. The reaction is usually carried out at a temperature of -80 to -50 ° C, preferably at -70 ° C in a suitable organic solvent, for example tetrahydrofuran or diethyl ether, under an inert gas atmosphere, for example nitrogen or argon.

Compounds of formula (IX) or (X) may also be prepared by reacting a compound of formula (VIII) or (IX) with an approximately equivalent amount of a suitable base, for example sodium hydride, followed by alkylation of the resulting carbanion in situ. with a suitable alkylating agent. The reaction is typically carried out at 0 ° C to room temperature in a suitable organic solvent, for example N, N-dimethylformamide.

The alkylation of compounds of formulas VIII or IX is carried out under conditions suitable for phase transfer, for example using a mixture of sodium hydroxide, water, chloroform, [CH ₃ (CH ₂ ) ₃ ] ₄ N ^{+ -} HSO ₄ and compounds of type (C ₁ - ( ₄ ) alkyl) Z ¹ , wherein Z ¹ is preferably an iodine atom, at a temperature of 0 ° C to room temperature, typically room temperature.

The epoxidation of the ketone of formula (IX) or (X) is carried out using conventional procedures, for example using dimethyloxosulfonium methylide according to J.A.C. (1965), 87, 1353, or using chloromethyl lithium according to Tet. Lett. (1986) 795.

3) Compounds of formula I wherein R, R ¹ , R ² and Y are as defined in formula I and X is N may be prepared according to Scheme 5.

-12GB 279339 B6

Scheme 5

reduction of a compound of formula I wherein X is N

In Scheme 5, R, R ¹ , R ² and Y have the meanings given in formula (I) and Z and Z are each independently hydrogen and a group which can be selectively removed by reduction, provided both are not simultaneously hydrogen atom. Z ² is preferably a group which can be selectively removed by reduction and Z is preferably hydrogen. Z is preferably removed by reduction, especially when it is a halogen atom, i.e. fluorine, chlorine, bromine or iodine, the most preferred being chlorine.

If it is a halogen atom, preferably chlorine, the reduction is preferably carried out by hydrogenolysis. Typically, the compound of formula I is subjected to hydrogenolysis using a suitable catalyst, for example palladium on charcoal, using a suitable solvent, for example ethanol, optionally in the presence of another suitable base, for example sodium acetate. The reaction may be carried out at room temperature to reflux temperature of 100 to 500 kPa, but the reaction also proceeds well at room temperature at atmospheric pressure.

An intermediate of formula XI in which one of Z ² and Z is hydrogen and the other is a group which can be selectively removed by reduction can be readily prepared according to Reaction Scheme 6.

Scheme 6

1) base, solvent compound ----------------------> formula XI (XII)

(III)

-135

In Scheme 6, R, R ¹ , R ² and Y are as defined in formula (I), one of Z ² and Z ³ is hydrogen and the other is selectively removable. The reaction may be carried out under similar conditions to those described for Scheme 1.

Intermediates of formula (XI) wherein one of Z ² and Z is hydrogen and the other group which can be selectively removed by reduction may also be prepared by procedures analogous to those described in Scheme 2.

The starting materials of formula (XII) may be prepared by conventional methods, which will be further elucidated in the following preparations.

Intermediates of formula XI wherein Z ² and Z ³ are groups which can be selectively removed by reduction can be obtained from groups analogous to the method of Reaction Scheme 2 using the appropriate starting materials of the epoxide type obtainable in a conventional manner as shown in the following Reaction Scheme 7.

Scheme 7

CO ₂ (C ₁ -C ₄ alkyl)

epoxidation

hydrolysis, alkylation decarboxylation

-14GB 279339 B6

Ί 9

In Scheme 7, R, R, R, and Y are as defined in formula (I). Z is a group which can be selectively removed by reduction, and Z ⁴ is a chlorine atom or a C 1 -C 4 alkoxy group.

All of the above reactions are of the conventional type, employing conventional reagents and reaction conditions. Methods for isolating the resulting products are also known from the literature and will be presented in the following examples.

Pharmaceutically acceptable acid addition salts can be readily obtained by mixing solutions containing the free base and the desired acid. The resulting salt precipitates out of solution easily and is then collected by filtration, or it can be separated by evaporation of the solvent.

The compounds of formula I and their salts are antifungal agents which can be used for the treatment and prophylaxis of fungal infections in animals, including humans. For example, these can be local infections in humans caused, inter alia, by Candida, Trichophyton, Microsporum, or Epidermophyton, or by mucosal infections caused by Candida albicans (e.g., oral infections in infants or vaginal infections). The compounds can also be used to treat systemic fungal infections caused by, for example, Candida (e.g., Candida albicans), Cryptococcus neofarmans, Asperfillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

The compounds of the invention have unexpectedly good activity against clinically important Aspergillus strains. In particular, unexpectedly good pharmacokinetic properties, which result in a longer half-life (t 1/2 values), provide this potency.

The in vitro potency of these compounds can be achieved by determining the minimum inhibitory concentration of m.i.c., that is, the concentration of the active compound in an environment where the growth of a particular microorganism no longer occurs. In practice, this assay is performed by inoculating agar plates, each containing the test substance at a certain concentration, with a standard culture, such as Candida albicans, and then incubating the plates at 37 ° C for 48 hours. The plates are then examined for the presence or absence of fungal growth and m.i.c. Other useful microorganisms are, for example, Aspergillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidiodes immitis and Torulopsis glabrata.

In vivo evaluation can be performed by administering the test substance intraperitoneally, intravenously or orally to mice inoculated with a strain, for example. Candida albicans or Aspergillus fumigatus. Efficacy is based on the survival of a treated group of mice after the death of untreated control mice. The dosage, which can provide a 50% protective effect against death is called PD _5Q. In the case of an Aspergillus infection, the number of mice cured of the infection is also evaluated.

-15GB 279339 B6

For human use, the active compounds of formula (I) and their salts may be administered per se, but are usually administered in admixture with a pharmaceutical carrier of choice depending on the intended route of administration and standard pharmaceutical procedures. For example, the compounds may be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules per se, or also with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. The compounds may be administered parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, a sterile aqueous solution is preferred, which may contain other substances, for example, salts or glucose, to provide isotonicity with the blood.

The aqueous solubility of the compound of formula (I) may be improved by complexing with a hydroxyalkyl derivative or cyclodextrin, thereby facilitating the manufacture of pharmaceutical compositions. All types of cyclodextrin, most preferably β-cyclodextrin, can be used for this purpose. The hydroxyalkyl derivative is preferably a hydroxypropyl derivative.

For oral and parenteral administration in humans, the daily dose of the antifungal compounds of formula I and their salts ranges from 0.01 to 20 mg / kg in single or divided doses for both oral and parenteral administration. The tablets or capsules may contain 5 to 0.5 grams of active ingredient, and may be administered singly or in two or more pieces, depending on the immediate need. The required dose, most appropriate for the patient, will be determined by the physician depending on the age, weight and response of the patient to the drug being administered. The above dosages are merely exemplary of average dosages, and it will be understood that higher or lower dosages may also be used in individual cases, and are within the scope of the invention.

The compounds of formula (I) may also be administered in the form of suppositories or pessaries, or topically in the form of suspensions, solutions, creams, ointments or powders. For example, they may be formulated as a cream consisting of an aqueous polyethylene glycol emulsion or liquid paraffin, or may be incorporated at a concentration of 1-10% into an ointment consisting of white wax or soft white paraffin using the necessary stabilizers and preservatives.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention, intermediates and processes for their preparation will be described in detail in the following by way of specific examples, which are illustrative only and are not intended to limit the scope of the invention in any way. The enantiomeric pairs B mentioned in these examples or preparations, as well as the products obtained according to Examples 1, 3, 4 and 5, in which only one of the two possible enantiomeric pairs were obtained each, represent a racemic mixture of 2R, 3S- and 2S, 3R ~.

-16GB 279'339 B6

Examples

Example 1

3- (3-Chloro-pyridin-4-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol

To a solution of diisopropylamine (1.01 g, 10 mmol) in anhydrous tetrahydrofuran (THF) (60 mL) at -60 ° C under a nitrogen atmosphere was added dropwise 6.25 mL (10 mmol) of n-butyllithium in hexane. The mixture was allowed to warm to -20 ° C, then re-cooled to -70 ° C and to the resulting solution of 10 mmol lithium diisopropylamide (LDA) was added dropwise 1.41 g, 10 mmol 3-chloro-4- at -70 ° C. ethylpyridine, obtained by DL Comins et al., Heterocycles, 22, 339 (1984). The resulting mixture was stirred at the same temperature for 15 minutes. and then a solution of 2.23 g, 10 mmol is added

1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone in 15 mL THF. The mixture was allowed to warm to room temperature over 30 minutes, then quenched by the addition of 30 mL of water and extracted with 3x60 mL of ethyl acetate. Combine the organic extracts, dry over magnesium sulfate, filter, concentrate in vacuo.

The resulting product was isolated by flash chromatography on a silica column eluting with ethyl acetate. The product was recrystallized from ethyl acetate to give the title product (0.46 g), m.p. 182-184 ° C.

Analysis for ^C 17 ^H 15 ^C1F 2 ^N ° 4 requires C 55.98, H 4.14, N 15.36% Found C, 55.76; H, 4.15; N, 15.23%.

Example 2

2- (2,4-Difluorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol

The reaction was carried out in a similar manner to Example 1 using 4-ethyl-3-fluoropyridine (the preparation of which is described in the following Preparation 1) instead of 3-chloro-4-ethylpyridine as starting material. The crude product was purified by silica column chromatography using ethyl acetate as eluent, the product containing fraction was reduced and evaporated to yield

-18CZ 279339 B6 consistently product as, enantiomeric pair A, m.p. 178-181 ° C, the identity of the product was verified - ^L-NMR spectrum.

A-NMR (CDC1 _3): δ 1.6 (d, 3H), 3.95 (q, 1H), 4.7 and 5.15 (AB q, 2H), 5.1 (s, 1H (OH), 6.5 (m, 1H), 6.95 (m, 1H), 7.45 (t, 1H), 7.8 (s, 1H), 7.95 (s, 1H) 8.15 (s, 1H); 8.25 (d, 1H) ppm.

A further elution of the column with 95: 5 ethyl acetate / methanol yielded the crude enantiomeric pair B after the combined fractions were combined and further purified by silica column chromatography using dichloromethane / methanol / 0.88%. aqueous ammonia (93: 7: 1). The appropriate fractions were combined and evaporated to give the title compound, enantiomeric pair B, m.p. 188-189 ° C after trituration with diethyl ether.

Analysis for C ₁₇ H ₁₅ F ₃ N ₄ O. 0.25 H ₂ O requires C 57.87 H 4.43 N 15.88 Found% C, 57.63; H, 4.32; N, 15.71%.

Enantiomeric pair B was separated by HPLC using CHIRACEL ^R OG chiral material, eluting with isopropanol / hexane (1: 1). Appropriate fractions were combined and evaporated to give the individual enantiomers contaminated with the chiral material used for resolution.

Each of these impure enantiomers was further purified by silica column chromatography using a 95: 5 mixture of dichloromethane and methanol as eluent. Appropriate fractions were combined and evaporated to give single pure enantiomers after trituration with hexane / diethyl ether.

This gave one enantiomer with a melting point of 57-59 ° C and an optical rotation of [α] ²⁵ D -59 ° (c = 1 mg / ml in methanol) and the other with a melting point of 56-57 ° C and an optical rotation of [α] [ ^Α ] ²⁵ D + 57 ° (c = 1 mg / mL in methanol).

Examples 3 to 6

The compounds mentioned in following table, general formula l / ^ N - = N. CH ₃ OH I || ^r _Y A.

Prepared in an analogous manner to Example 1, starting from the appropriate 4-ethyl-3-halopyridines and 1- (halophenyl-2- (1H-1,2,4-triazol-1-yl)). ethanone derivatives.

Y

1 ^α 3 (1) ΓΊ ( ² ) 166-167 c ₁₇ h ₁₆ cifn ₄ o k ^ calculated C 58.88, found C 58.92, H 4.65, N 16.16 * H 4.85, N 15.99%

c ₁₇ e ₁₆ of CIFN ₄ requires C 58.88, H 4.65, N 16.16 l Found: C 59.05, H 4.84, N 16.06%

156-157 ^C 17 ^H 16 ^F 2 ^N 4 ° H, 4.88; N, 16.96 Found C 61.45, H 4.96, N 16.85

-20EN 279339 B6 melting point analysis ^C C

F

enantiomeric c ₁₇ h ₁₆ dig ₄ oh ₂ o pair A: 112-114 calculated C 55.97, H 4.97, found C 56.06, H 4.94, N, 15.36 š N 15.42 *

enantiomeric C ^ HH ^CIFN ^O pair B: C, 58.88; H, 4.65; N, 16.16.

184-185 found C 59.17, H 4.63, N 16.15 L

Explanatory notes to the table:

(1) Chromatography was carried out on a silica column using ethyl acetate / dichloromethane (2: 1) and then ethyl acetate as eluent. The resulting solid was triturated with diethyl ether to give the desired product.

(2) The starting material is described in Example 1.

(3) The starting material is described in Preparation 1.

(4) Chromatography was carried out on a silica column, which was eluted first with a 2: 1 mixture of ethyl acetate and dichloromethane and then with ethyl acetate. The fractions were combined and evaporated and the resulting material was further purified on a silica column using dichloromethane / methanol 0.88% aqueous ammonia (93: 7: 1). The fractions were combined and evaporated and the residue triturated with diethyl ether to give the desired product.

(5) The enantiomeric pair was separated by HPLC in analogy to Example 2. This gave single enantiomers, one with a melting point of 83-84 ° C and an optical rotation [α] ²⁵ _D = -80 ° (c = mg / ml) in methanol), and a second with an optical rotation [α] ²⁵ _D = + 82 ° (c = 1 mg / ml in methanol) and a melting point of 78-79 ° C.

(6) Chromatography was carried out on a silica column at. using hexane / isopropanol / 0.88% aqueous ammonia (80: 20: 1.5) as eluent. Appropriate fractions were combined and evaporated and the material was further purified on a silica column using a 97: 3 mixture of ethyl acetate and ethanol. Separate enantiomeric vapors were obtained after decanting and evaporating the fractions, each of which was triturated with diethyl ether to give the desired product.

(7) Enantiomeric pairs were separated by HPLC as in Example 2.

Example 7

2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol

A solution of 0.307 g, 0.8 mmol

3- (4-Chloro-5-fluoropyrimidin-6-yl) -22EN 279339 B6

Solution 0.307 g, 0.8 mmol 3- (4-chloro-5-fluoropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) of butan-2-ol as enantiomeric pair B (Preparation 2 (iii)) in 20 ml of ethanol is hydrogenated at atmospheric pressure at room temperature in the presence of 30 mg of 10% palladium on charcoal and 0.082 g, 1 mmol of sodium acetate. After 5 hours, 10 mg of 10% palladium on charcoal was added and hydrogenation was continued for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica eluting with ethyl acetate / methanol (97: 3), the resulting fractions combined, evaporated and triturated with diethyl ether to give 0.249 g of the title compound as an enantiomeric product (89%). steam B with a melting point of 127 ° C.

Analysis for C ₁₆ H ₁₄ F ₃ N ₅ O Calculated: C, 55.01; H, 4.01; N, 20.05 Found% C, 55.08; H, 4.00; N, 19.96%.

A sample of 0.105 g, 0.3 mmol of the resulting enantiomeric pair B and 0.07 g, 0.3 mmol of IR - (-) - 10-camphorsulfonic acid was dissolved in 4 mL of methanol and the solution was cooled to 0 ° C for 2 hours. The resulting crystalline solid was collected by filtration to give 0.6 g of 1R - (-) - 10-camphosulfonate 2R, 3S-2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) - 1- (1 H -1,2,4-triazol-1-yl) butan-2-ol. 0.5% methanol, m.p. 176 ° C. Optical rotation [α] ²⁵ _D = -49.5 ° (c = 2 mg / ml in methanol).

Analysis for C ₂ gH QF _{3 3} N ₃ O ₃ S.0,5 _CH3 OH Calculated C, 53.27; H, 5.36; N, 11.73% Found: C 53.09, H 5.36, N 11, 43%.

The absolute configuration of this compound was confirmed by X-ray crystal analysis.

The filtrate after crystallization was evaporated in vacuo and the residue was partitioned between 10 mL of dichloromethane and 5 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue, together with 0.46 g, 0.2 mmol of 1S - (+) - 10-camphorsulfonic acid, was dissolved in 3 ml of methanol and the solution was cooled to 0 ° C for 2 hours. The crystalline solid was then filtered off to give 0.052 g of 2S, 3R-2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1S - (+) - 10-camphosulfonate) -1- (1 H -1,2,4-triazol-1-yl) butan-2-ol. 0.5% methanol, m.p. 176 ° C. Optical rotation [α] ²⁵ _d + 54.5 ° (c = 2 mg / ml in methanol).

Analysis for ^C 26 ^H 30 ^F 3 ^N 5 O5 ^S · ° ^{'5 CH} 3 ^0H requires C 53.27, H 5.36, N 11.73% Found C 53.27, H 5.31, N 11, 64%.

A sample of the IR - (-) - 10-camphosulfonate (1.22 g, 2.1 mmol) prepared above was partitioned between 20 mL of dichloromethane and 3 mL of saturated aqueous sodium bicarbonate.

-23E 279339 B6 was filtered and evaporated in vacuo to give 0.64 g of 2R, 3S-2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-l, 2,4-triazol-1-yl) butan-2-ol, m.p. 127 ° C. Optical rotation [α] ²⁵ _D - 62 ° (c = 1 mg / ml in methanol).

A sample of 1.17 g (2.0 mmol) of 1S - (+) - 10-camphosulfonate obtained as described above is treated in a similar manner to 1R - (-) - 10-camphosulfonate above to give 0.63 g of 2S, 3R-2-

4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, m.p. 127 ° C. Optical rotation [α] ²⁵ _D + 59.5 ° (c = 2 mg / ml in methanol).

Example 8

2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, enantiomeric pair B

1) [(CH ₃ ) ₃ Si] ₂ N Na, THF

-24GB 279339 B6

To 200 mL of THF was added 79 mL of a 1.0 M solution of sodium bis- (trimethylsilyl) amide in THF and the solution was cooled to -65 ° C under nitrogen. Then a solution of 10 g of 4-ethyl-5-fluoropyrimidine (preparation 8) in 100 ml of THF was added over 30 minutes. The mixture was stirred at -65 ° C for 3 hours and then the slurry was treated with 100 mL of a solution of 17.7 g of 1- (2,4-difluorophenyl) -2- (1H-1,2,4-triazole-1- yl) ethanone in 100 ml THF, the solution is added dropwise over 30 minutes. The solution was stirred at -65 ° C for 1 h and then 20 mL of acetic acid was added. The mixture is warmed to -20 ° C, washed with 200 ml of water, the organic layer is separated and mixed with 200 ml of ethyl acetate aqueous phase extract. The organic layers were combined and evaporated under reduced pressure to give a solid, which was triturated with 230 ml diethyl ether and filtered. The filtrate was evaporated under reduced pressure and the residue was chromatographed on a silica column using diethyl ether / ethyl acetate 1: 1. The product fractions were combined, evaporated under reduced pressure and the residue chromatographed on a silica column as eluent. The product fractions were combined and evaporated under reduced pressure to give 0.82 g of pure title compound, m.p. 125-127 ° C.

H, 4.01; N, 20.05 Found: C, 54.89; H, 4.06; N, 19.66%.

Example 9

2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, enantiomeric pair A

The title compound was prepared in a manner analogous to EXAMPLE 7 starting with 3- (4-chloro-5-fluoropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1). (2,4-triazol-1-yl) butan-2-ol, enantiomeric pair A (Preparation 2 (iii)). M.p. 137 ° C.

Analysis for ^C i6 ^H 14 ^F 3 ^R ° 5 requires C 55.01, H 4.01, N 20.05 Found% C, 54.89; H, 4.06; N, 19.82%.

Example 10

3- (5-chloropyrimidin-4-yl) -2- (2,4-difluorophenyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol, enantiomeric pair B)

-25GB 279339 B6 h ₂ , 10% Pd / C

CH ₃ CO ₂ Na,

------------: ----------------->

No. ₂ h ₅ ° ^h

A solution of 0.58 g, 1.46 mmol of 3- (4,5-dichloropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) of butan-2-ol, enantiomeric pair B (Preparation 6 (iii)) in 20 ml of ethanol is hydrogenated at atmospheric pressure at room temperature in the presence of 45 mg of 20% palladium on charcoal and 122 mg, 1.5 mmol total sodium acetate 7 hours. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue was flash chromatographed on silica eluting with ethyl acetate, and the product fractions were combined and evaporated to give 0.35 g (72%) of the title product, mp 128 ° C.

Analysis for ^C 16 ^H 14 ^C1F 2 ^N 5 ° · ° '° ^{3 H} 2 Calculated: C 51.76 H 3.94 N 18.87 Found% C, 51.68; H, 3.89; N, 18.58% .

-26GB 279339 B6

Example 11

3- (5-chloropyrimidin-4-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, enantiomeric pair A

The resulting product was obtained in a manner analogous to Example 10, starting with 3- (4,5-dichloropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2). 4-triazol-1-yl) butan-2-01, enantiomeric pair A (preparation 6 (iii)).

In this way a rubbery product is obtained, the _{vv of} which has been verified by 1 H-NMR spectroscopy.

¹ H-NMR (CDCl ₃ ) δ: 1.50 (d, 3H), 4.4 (q, 1H), 4.67 and 4.82 (AB q, 2H), 6.35 (s, 1H ( OH), 6.45 (m, 1H), 6.62 (m, 1H), 7.07 (m, 1H), 7.6 (s, 1H), 8.05 (s, 1H), 8 Δ (s, 1H), 8.8 (s, 1H) ppm.

Examples 12 to 16

Compounds of formula (I) prepared by the process of the invention and represented by the following general formula:

CHΝ 'can be obtained as described in Example 10, starting from the appropriate 2-aryl-3- (4-chloro-5-fluoropyrimidin-6-yl) -1- (1H-1,2) materials (4-triazol-1-yl) butan-2-ol derivatives.

The meanings of the symbols R, melting point and analytical data for the compounds of Examples 12-16 are given in the following table:

-27GB 279339 B6 Example no.

12 mm ( ¹ )

enantiomeric melting point analysis C c ₁₆ H ₁₅ F ₂ N ₅ O calculated C 58.01, H 4.53, N 21.15% found C 58.17, B 4.68, N 21.12 l

13 < ² )

117 ^C 16 ^B 15 ^F 2 ^N 5 ° calculated C 58.01, H 4.53, N 21.15% found C 58.22, B 4.68, N 21.10 1

103 - 104 C ₁₆ H ₁₅ ClFN ₅ O calculated C 55.26, B 4.35, N 20.14% found C 55.58, B 4.30, N 20.05 l

121 - 122 C ₁₆ H ₁₅ ClFN ₅ O calculated C 55.26, B 4.35, N 20.14 found C 55.53, B 4.25, N 20.16 I

150 - 152 C ₁₆ H ₁₄ Cl ₂ FN ₅ O calculated C 50.28, H 3.69, N 18.32 found C 50.23, H 3.61, N 18.13%

(1) Chromatography is carried out on a column of silica, eluting with an ethyl acetate / methanol (96: 4) mixture.

(2) Chromatography is carried out on a silica column using isobutyl methyl ketone as the eluent.

(3) Default substance se gains according to preparation 3. (4) Default substance se gains according to preparation 4. (5) Default substance se gains according to preparation 5.

(6) The enantiomeric pair obtained is separated by HPLC using the method of Example 2.

Example 17

2R, 3S-2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol solution and hydroxypropyl-β-cyclodextrin in aqueous sodium chloride solution g of hydroxypropyl-β-cyclodextrin (molar substitution = 0.41) is placed in a 10 ml flask and dissolved in 7 ml of distilled water. 90 mg of sodium chloride are added, the salt is dissolved in the solution and the volume is made up to 10 ml with distilled water. The resulting solution was added to 100 mg of 2R, 3S-2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol (Example 7) in a vial, the mixture is sonicated for 15 minutes and then blended by mechanical rotation of the vial for two days. Another 200 mg of hydroxypropyl-β-cyclodextrin was added and the mixture was stirred for 1 hour by mechanical rotation of the vial to give the resulting solution.

The preparation of some of the new starting materials used in the Example section will be explained in the following preparations:

Preparation 1

4-ethyl-3-fluoropyridine

1) LDA, THF

2) C ₂ H ₅ I

To a stirred solution of LDA (200 mmol) in anhydrous THF (40 mL) (prepared as described in Example 1) at -70 ° C was added dropwise 20 g (200 mmol) of 3-fluoropyridine under nitrogen. After 30 minutes at the same temperature is added

Ethyl iodide (370 g, 370 mmol) was added dropwise, and the mixture was allowed to slowly warm to -10 to -5 ° C, resulting in an exothermic reaction, and the temperature spontaneously increased to 15 to 20 ° C. After stirring for a further 30 minutes, the reaction is quenched by the addition of 50 ml of water and the organic phase is separated. The aqueous phase was extracted with ether (3.times.50 ml), the organic layers were combined, dried (MgSO4) and evaporated under reduced pressure. The resulting liquid was distilled at atmospheric pressure to give 13 g of the title compound, b.p. 154-158 ° C. This material was characterized by ¹ H-NMR spectrum.

¹ H-NMR (CDCl ₃ ): δ 1.25 (t, 3H, J = 10Hz), 2.65 (q, 2H, J = 10Hz), 7.1 (t, 1H, J = 8Hz) 8.3 (d, 1H, J = 8Hz), 8.33 (s, 1H) ppm.

Preparation 2

3- (4-Chloro-5-fluoropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol

-30GB 279339 B6

CH, f

OCH ₂ CH ₃

1) CH ₃ ONa, ch ₃ oh ------------------------->

2)

(ii)

-31GB 279339 B6

To a solution of sodium methoxide (8.64 g, 160 mmol) in methanol (50 mL) at 0 ° C was added a solution of ethyl .alpha.-fluoropropylacetate (12.96 g, 80 mmol) obtained from E. D. Bergmann et al., J. Chem. Soc., 1959, 3278 and D. J. Burton et al., Tet. Lett., 30, 6113 (1989), and 8.32 g, 80 mmol of formamidine acetate in 50 mL of methanol, and the resulting mixture was stirred at 0 ° C for 1 hour, then at room temperature overnight, and finally at reflux for 30 minutes. reflux condenser. The mixture was cooled and excess sodium methoxide was neutralized by the addition of 10 g glacial acetic acid. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in hot ethyl acetate, the insoluble sodium acetate was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate as eluent, the appropriate fractions were combined and evaporated and the residue triturated with diethyl ether to give 5.5 g of the title product (48%), mp 105-106 ° C.

Analysis CGH ₇ FN ₂ O Calculated C, 50.70; H, 4.93; N, 19.72 Found% C 50.38 H 4.85 N 19.63%.

The same material can also be obtained as described in Preparation 7.

i) 4-chloro-6-ethyl-5-fluoropyrimidine

A mixture of 6.4 g (45 mmol) of the product of step (i) and 30 ml of phosphoryl chloride was heated at reflux for 3 hours. Excess phosphoryl chloride was removed by distillation under reduced pressure and the residue was poured into a mixture of water and crushed ice. The resulting mixture was extracted with 3x50 mL of methylene chloride, the organic extracts were combined, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting oil was distilled under reduced pressure to give 4.81 g (66%) of b.p. 74 ° C at 3 kPa. The product was characterized by _xx filtering by 1 H-NMR spectrum.

¹ H-NMR (CDCl ₃ ): δ 1.3 (t, 3H, J = 10 Hz), 2.9 (q, 2H, J = 10 Hz), 8.68 (S, 1H) ppm.

(iii) 3- (4-chloro-5-fluoropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butane-2- ol

To a solution of 20 mmol of LDA in 50 mL of THF (prepared as in Example 1) under a nitrogen atmosphere at -70 ° C was added dropwise a solution of 3.2 g, 20 mmol of the product of step (ii) in 30 mL of THF within 15 minutes. Toluene may also be used in place of THF in the preparation of this mixture. The resulting mixture was stirred at the same temperature for 3 hours and then a solution of 4.46 g, 20 mmol of 1- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone in ethanol was added. 50 ml THF and the mixture was maintained at -70 ° C for 1 hour and then at -50 ° C for an additional hour. The reaction was quenched by the addition of a solution of glacial acetic acid (1.2 g) in water (10 ml) and allowed to warm to room temperature. The organic phase was separated / the aqueous phase was extracted with 20 ml

-32GB 279339 B6. The organic phase is separated, the aqueous phase is extracted with 20 ml of ethyl acetate, the organic layers are combined, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on a column of silica using a 3: 2 mixture of ethyl acetate and diethyl ether, the fractions combined and evaporated and the residue triturated with diethyl ether to give 0.94 g of the enantiomeric pair B of the title product in 12% yield. mp 92 ° C.

Analysis for C ₁₆ H ₁₃ C1F ₃ N ₅ O requires C 50.06, H 3.39, N 18.25% nalezenoC 49.93, H 3.57, N 18.17%.

Further elution gave the enantiomeric pair A of the title compound contaminated with the ketone starting material after pooling and evaporation of the appropriate fractions. This product was purified by repeated recrystallization from diethyl ether to give the title product, m.p. 132 ° C.

Analysis for C ₁₆ H ₁₃ C1F ₃ N ₅ O requires C 50.06, H 3.39, N 18.25% found C 49.93, H 3.58, N 18.23%.

Preparations 3 to 5

Compounds of the following general formula

were prepared in a manner analogous to Preparation 2 (iii) using 4-chloro-6-ethyl-5-fluoropyrimidine and the corresponding 1-aryl-2- (1H-1,2,4-triazol-1-yl) ethanone derivatives as starting materials.

-33EN 279339 B6 preparation R enantiomeric temperature melting pair analysis ‘C

C ₁₆ H ₁₄ ClF ₂ N ₅ O calculated C 52.53, H 3.83, N 19.15% found C 52.22, H 3.92, N 19.08l

H, 3.83; N, 19.15 Found: C, 53.17; H, 4.00; N, 19.27.

(B)

118-119 C _g H ₁₄ Cl ₂ FN ₅ O requires C 50.28 H 3.69 N 18.32 I 50.65 Found: C, H, 3.71, N, 18.12 s

119 - 120 C ₁₆ H ₁₄ Cl ₂ FN ₅ O calculated C 50.28, H 3.69, N 18.32 found C 50.54, H 3.71, N 18.16%

Cl

123 - 124 C ₁₆ H ₁₃ C ₃ FN ₅ O calculated C 46.12, H 3.05, N 16.81 l found C 46.49, H 3.05, N 16.69 L

-34GB 279339 B6

Preparation 6

3- (4,5-dichloropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol (i) 6 ethylpyrimidin-4 (3H) -one

(i)

(i) 6-ethylpyrimidin-4 (3 H) -one

To a solution of 4.19 kg, 77.6 moles of sodium methoxide and 3.0 kg, 28.8 moles of formamidine acetate in 45 liters of methanol at 5-10 ° C is slowly added a solution of 2.5 kg of methylpropionylacetate in 10 liters of methanol, the temperature is kept below 20 ° C during the addition. The resulting mixture was stirred overnight at room temperature and then adjusted to pH 7 by addition of concentrated hydrochloric acid. The reaction mixture is concentrated under reduced pressure to a volume of approximately 10 liters, diluted with 10 liters of water and extracted with 2x30 L of 2-butanone. The organic extracts were combined and evaporated under reduced pressure to approximately 2 L and the solution was diluted with 4 L of ethyl acetate. 2.4 kg of the title compound crystallized from the solution in 70% yield, which was recrystallized from isopropanol to give the product, m.p. 132-134 ° C.

Analysis for C ₆ H ₈ N ₂ O requires C 58.05, H 6.50, N 22.57% Found C, 58.45; H, 6.37; N, 22.41%.

(ii) 4,5-dichloro-6-ethylpyrimidine

To a solution of 18.6 g (150 mmol) of 6-ethylpyrimidin-4 (3H) -one from step (i) in 120 ml of concentrated hydrochloric acid is added dropwise at 30 to 40 ° C 18 ml of a 30% hydrogen peroxide solution 30 minutes. The reaction is slightly exothermic, the resulting mixture is stirred overnight at 40 ° C and then evaporated under reduced pressure and the residue is suspended or dissolved in toluene and the toluene is then removed under reduced pressure.

The residue is dissolved in 150 ml of phosphorus oxychloride and the solution is refluxed for 3 hours, then the phosphorus oxychloride is evaporated under reduced pressure. The residue was poured into ice-water and extracted with methylene chloride (3x50 ml). The organic extracts were combined, washed with 30 ml of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting oil was distilled under reduced pressure to give 5.4 g (20% yield) of product, bp 104 ° C at 3 kPa, characterized by 1 H-NMR spectroscopy.

¹ H-NMR (CDCl ₃ ): δ 1.3 (t, 3H, J = 10 Hz), 3.04 (g, 2H, J = 10 Hz), 8.75 (s, 1H) ppm.

(iii) 3- (4,5-dichloropyrimidin-6-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol

To a solution of LDA (13.6 mmol) in THF (50 ml) prepared as described in Example 1 was added dropwise 2.35 g (13.3 mmol) of 4,5-dichloro-6-ethylpyrimidine from step (ii) at -70 ° C. and the resulting solution was stirred at the same temperature for 10 minutes. Then a solution of 2.97 g, 13.3 mmol of 1- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone in 50 mL of THF was added to the reaction mixture so rapidly The reaction mixture was stirred at -70 ° C for 1 hour and at -50 ° C for a further 1 hour, then quenched by the addition of 11 mL of a 10% aqueous acid solution.

-36GB 279339 B6 acetic. The organic phase is separated, the aqueous phase is extracted with 2x20 ml of ethyl acetate, the organic layers are combined, dried over magnesium sulphate and then the solvent is evaporated off under reduced pressure, the residue is triturated with 25 ml of diethyl ether and 1.7 g of unreacted starting ketone is filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed on a silica column using ethyl acetate / diethyl ether, the appropriate fractions combined and evaporated and the residue triturated with diethyl ether to give 670 mg of enantiomeric pair B as a solid in 13% yield. mp 124 ° C.

Analysis for ^C 16 ^H 13 ^{C 1 F} 2 ^N 2 ° 5 requires C 48.00, H 3.25, N 17.50% Found C, 47.78; H, 3.33; N, 17.13%.

After further elution, pooling and evaporation of the appropriate fractions and trituration of the residue with diethyl ether, a total of 527 mg of enantiomeric pair A was obtained in a yield of 10% as a solid with a melting point of 137 ° C.

Analysis for ^C 16 ^H 13 Cl ₂ F ₂ N ₅ calcd for C 48.00, H 3.25, N 17.50 Found% C, 48.02; H, 3.30; N, 17.39%.

-37GB 279339 B6

Preparation 7

6-Ethyl-5-fluoropyrimidin-4 (3H) -one (i)

2,4-dichloro-5-fluoropyrimidine

poci ₃ , c ₆ h ₅ n (ch ₃ ) ₂

------------------—>

(ϋ) (i) CH ₃ CH ₂ MgBr,

DME, THF ii) AcOH

IN

(iii) <------------ aqueous KMnO ₄

(iv) aqueous NaOH V

(in)

H ₂ , CH ₃ CO ₂ Na,

/Α / c, c ₂ h ₅ oh

-38EN 279339 B6 (i) 2,4-dichloro-5-fluoropyrimidine

To 141.4 g of phosphorus oxychloride was added 20 g of powdered 5-fluorouracil at 25 ° C. The resulting suspension was heated to 90 ° C and 37.3 g of Ν, Ν-dimethylaniline was added over 1 hour. The reaction was heated at reflux for 5 hours, after which 70 g of phosphorus oxychloride was distilled off. The mixture was cooled to 25 ° C, poured into 200 mL of 3N hydrochloric acid at 0 ° C in portions over 1 hour. The resulting product was then extracted from a mixture of 2 x 70 mL of dichloromethane. The extracts were combined, washed with 50 ml of water and evaporated in vacuo to 24 g of oil, which was analyzed by 1 H-NMR and mass spectrometry.

¹ H-NMR (CDCl ₃ ): δ 8.5 (s, 1H) ppm.

MS: m / e = 166.

(ii) 2,4-dichloro-1,6-dihydro-6-ethyl-5-fluoropyrimidine

To 4.27 g of magnesium shavings in 56 mL of THF was added a solution of 19 g of bromoethane in 19 mL of THF over 5 hours. A solution of 24 g of the product of step (i) in 70 ml of 1,2-dimethoxyethanol was added over 1 hour at 0 ° C. The reaction is then stopped at 10 DEG C. by the addition of 10 g of glacial acetic acid to give a solution of the title product which is used directly in the next step.

(iii) 2,4-dichloro-6-ethyl-5-fluoropyrimidine

To the solution obtained in the previous step, a solution of 23 g of potassium permanganate in 260 ml of water was added over a period of 2 hours, maintaining the temperature of the reaction mixture below 20 ° C. Then, 30 ml of 5N hydrochloric acid and a solution of 14 g of sodium metabisulfite in 42 ml of water are added successively. After decolorizing the mixture, the product was extracted with 250 ml of ethyl acetate. The organic layer was then evaporated to an oil which was partitioned between 50 mL of dichloromethane and 105 mL of 2N sodium hydroxide solution and the organic layer was washed with 100 mL of 5% sodium chloride solution. The organic layer was evaporated to give a product solution which was used directly in the next step.

(iv) 2-chloro-6-ethyl-5-fluoropyrimidin-4 (3 H) -one

To the solution from the previous step was added 6 mL of water. The mixture was stirred at 80 ° C and 45 ml of 4N sodium hydroxide solution was added slowly over 2 hours. After the addition was complete, the reaction mixture was cooled and washed with 15 mL of dichloromethane. The aqueous layer was then added to 60 mL of dichloromethane and the pH was adjusted to 1 by addition of concentrated hydrochloric acid. The organic layer was separated and the pH was adjusted to 3 by addition of concentrated aqueous ammonia. The precipitated ammonium chloride is filtered off, the filtrate is evaporated to a volume of 15 ml and diluted with 150 ml of ethyl acetate. The solution was evaporated to a volume of 30 ml and the resulting crystals were collected by filtration and dried to give 8 g of product which was analyzed by 1 H-NMR and mass spectrometry.

-39C 279339 B6 ¹ H-NMR (DMSO-d 6): δ 7.3 (exchangeable), 2.4 (m, 2H), 1.1 (t, 3H) ppm.

Mass spectrometry: m / e = 176.

(v) 6-ethyl-5-fluoropyridin-4- (3H) -one

To 6 g of the product of part (iv) in 60 ml of ethanol was added 5.5 g of sodium acetate and 0.6 g of 5% palladium on charcoal. The mixture was hydrogenated at 0.3 MPa for 8 hours. The catalyst is filtered off, the filtrate is evaporated to a volume of 10 ml and then mixed with 2 ml of water and 80 ml of dichloromethane. Toluene (32 ml) was added and the solution was evaporated to a volume of 5-6 ml and then toluene (8 ml) was added. The resulting product crystals are filtered off, yielding 3.9 g of crystalline product which is analyzed by ¹ H-NMR and also by mass spectrometry.

¹ H-NMR _(DMSO-dg): δ 8.0 (s, 1H), 2.5 (m, 2H), 1.15 (t, 3H).

Mass spectrometry: m / e = 142.

Preparation 8

4-ethyl-5-fluoropyrimidine

H ₂ , Pd / C

--------->

CH ₃ CO ₂ Na, ch ₃ oh

A mixture of 10 g 2,4-dichloro-6-ethyl-5-fluoropyrimidine from Preparation 7 (iii), 8.83 g sodium acetate, 2 g 5% palladium on activated carbon 50% wet and 30 ml methanol is hydrogenated at 50 ° C and 0.3 MPa for a total of 5 hours. The resulting suspension was carefully filtered through a pad of cellulose with adjuvant, washed with 5 ml of methanol and the resulting orange filtrate was distilled at 64 ° C at atmospheric pressure to give a colorless distillate which was partitioned between 300 ml of water and 40 ml of ether and both the phases are separated. The organic phase was washed with water (4.times.50 ml), dried (MgSO4) and then the solvent was evaporated at room temperature under reduced pressure to give the title compound as a pale yellow liquid (2.2 g).

-40GB 279339 B6

CO ₂ CH ₂ CH ₃

Preparation 9

2-chloro-4-ethyl-5-fluoropyrimidine

ch ₃ ch (co ₂ ch ₂ ch ₃ ) ₂

NaH, THF (i) CH ₃ —CO ₂ CH ₂ CH ₃

(ii) aqueous HCl, ch ₃ every ₂ h

IN

(i) 2-Methyl-2- (2-chloro-5-fluoropyrimidin-4-yl) -1,3-propanedioic acid diethyl ester

2.8 g of a 60% sodium hydride dispersion in oil and 6 g of diethyl methyl malonate are reacted in 200 ml of THF at -10 ° C. After 30 minutes, a solution of 5 g of 2,4-dichloro-5-fluoropyrimidine from Preparation 7 in 25 ml of THF was added over 30 minutes at -10 ° C. The reaction mixture was partitioned between 200 mL of dichloromethane and 200 mL of water, acidified with aqueous acetic acid and the layers separated. The organic layer was evaporated under reduced pressure to an oil which was chromatographed on silica gel using dichloromethane as eluent. 9 g of the title compound are obtained after concentration and concentration of the appropriate fractions, which is analyzed by ¹ H-NMR and mass spectrometry.

¹ H-NMR (CDCl ₃ ): δ 8.5 (d, 1H), 4.6 (m, 4H), 1.9 (s, 3H), 1.3 (t,

3H) ppm.

Mass spectrum: m / e = 304.

(Ii) 2-chloro-4-ethyl-5-fluoropyrimidine

Dissolve 3.2 g of the product of (i) in 25 ml of acetic acid and dilute the solution with 10 ml of 5N hydrochloric acid. The mixture was heated at 100 ° C for 16 h. The mixture was cooled and partitioned between 30 mL of water and 45 mL of dichloromethane. The dichloromethane layer was separated, dried and evaporated under reduced pressure to give an oil which was chromatographed on silica gel using dichloromethane as eluent. The product was analyzed by ¹ H-NMR and mass spectrometry. Yield: 350 mg.

¹ H-NMR (CDCl ₃ ): δ 8.4 (s, 1H), 2.9 (m, 2H), 1.3 (t, 3H) ppm. Mass spectrum: m / e = 160.

Determination of in vivo efficacy of the compounds of the invention against Aspergillus fumigatus in mice

Using the general procedure described above, a group of test mice are inoculated with Aspergillus fumigatus. All mice are then treated with test substances, maintaining a standard dose of 20 mg / kg, for a total of five days. The results of these experiments in mice were evaluated on day 10.

The efficacy of the individual compounds is determined by the survival of the mice in the treated group after the death of the control group, as well as the number of mice recovered from the infection.

The results obtained in the comparative experiment using two compounds of the invention, Example 2 and Example 7, and using the two compounds described in European Patent Application No. 89307920.2, (EP-A-0357241) are summarized. in the following table:

Explanatory notes to the table:

Mice that were completely free of infection on day 10 were considered to be cured.

2. Although not cured in the above cases, the progression of the infection has been significantly reduced.

Test substance survival pattern (expressed in number of five mice) cure> (expressed in number of five mice) Example 2 enantiomeric pair B

5/5

Example 7 enantiomeric pair B Example 2, diastereomeric pair B of EP No. 89307920.0

Survival (expressed in number from group of five mice) cure (expressed in number from group of five mice) test substance of formula Example 3,. diastereomeric pair B of EP no.

89307920.2

3/5

0/5 (2)

PATENT CLAIMS

Claims (11)

Triazole derivatives of the general formula I (I) in which: R is phenyl substituted with 1 to 3 substituents, each of which is independently selected from the group consisting of halogens, -CF _3, and -OCF ₃ , R ¹ represents an alkyl group having 1 to 4 carbon atoms, R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, X is CH or N, and Y represents a fluorine atom or a chlorine atom; or a pharmaceutically acceptable salt thereof. -44GB 279339 B6 The triazole derivative according to claim 1, wherein R represents a phenyl group substituted with 1 or 2 halogen substituents. The triazole derivative according to claim 2, wherein R represents a phenyl group, substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and chlorine. The triazole derivative according to claim 3, wherein R represents 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl. The triazole derivative according to claim 4, wherein R represents 2-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl. A triazole derivative according to any one of claims 1 to 5, wherein R 1 represents a methyl group. A triazole derivative according to any one of the preceding claims 1 to 7 6 wherein R represents a hydrogen atom or a methyl group. The triazole derivative according to claim 7, wherein R ² is a hydrogen atom. The triazole derivative according to any one of the preceding 8, wherein X represents a nitrogen atom. A triazole derivative according to any of the preceding 9, wherein Y represents a fluorine atom. A triazole derivative according to any one of the preceding claims, from claims 1 to claims 1 to claims 1 to 11 10, wherein R ² represents a hydrogen atom, the compound having the 2R, 3S-configuration, i.e. A triazole derivative according to claim 1, selected from the group consisting of: 2R, 3S-2- (2,4-difluorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, 2R, 3S-2- (2-chlorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, -45GB 279339 B6 2R, 3S-2- (2-fluorophenyl) -3- (3-fluoropyridin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,